Preparation of optically active amines

ABSTRACT

A process for preparing optically active amines, a process for preparing racemic amines which can be resolved using optically active carboxylic acids or enzymes, and racemic and optically active amines and optically active amides are described.

The present invention relates to a process for preparing opticallyactive amines. Furthermore, the invention relates to a process forpreparing racemic amines which can be resolved using optically activecarboxylic acids or enzymes. Moreover, the invention relates to racemicand optically active amines and optically active amides.

Racemate resolution of amines by enzyme-catalyzed reaction with esters,like the classical chemical racemate resolution via formation ofdiastereomeric salts using optically active carboxylic acids (AdvancedOrganic Chemistry, Reactions, Mechanisms and Structure, Jerry March,Fourth Edition, John Wiley & Sons, Inc., 1992, ISBN 0-471-60180-2), isknown. Thus, Kitaguchi et al. (J. Amer. Chem. Soc. 111 (1989),3094-3095), for example, describes racemate resolution of amines usingtrifluoroethyl butyrate under subtilisin catalysis. However, theenantioselectivity of this reaction is highly solvent-dependent. Evenwhen the most suitable of the solvents described (3-methyl-3-pentanol)is used, the selectivity achieved is only moderate.

WO 91/19002 describes a process for chiral enrichment of asymmetricprimary amines where the amines are reacted with ethyl acetate or ethylbutyrate under subtilisin catalysis. However, the enantiomeric excessesachieved are unsatisfactory; moreover, long reaction times of from oneto a number of weeks are required.

Gotor et al. (J. Chem. Soc. Chem. Commun. (1988), 957-958) describe theenantioselective acylation of 2-amino-butan-1-ol with ethyl acetateunder catalysis with porcine pancreas lipase (PPL). Here, the ester used(ethyl acetate) also acts as solvent. If other solvents or other enzymesare used, the results are unsatisfactory.

Brieva et al. (J. Chem. Soc. Chem. Commun. (1990), 1386-1387) describethe enantioselective synthesis of amides from racemic primary amines byreaction with 2-chloropropionate under subtilisin catalysis in hexane orCandida cylindracea lipase catalysis in 3-methyl-3-pentanol.

Quiros et al. (Tetrahedron: Asymmetry 4 (1993), 1105-1112) describe thelipase-catalyzed synthesis of optically active amides from racemicα-halo-substituted ethyl propionates and primary amines. However, theenantioselectivity achieved in this reaction is unsatisfactory.

Asensio et al. (Tetrahedron Letters 32 (1991), 4197-4198) describe thelipase-catalyzed enantioselective acylation of secondary amines.However, this reaction is enantioselective only for one amine, and eventhere with only moderate results. Other amines are not enantioselectiveat all.

U.S. Pat. No. 5,057,607 describes the N-acylation of 3-amidoazetdinone[sic] compounds with the aid of penicillin G amidase. However,penicillin G amidase has a very limited substrate range, so that it canonly be used for preparing β-lactams.

WO 95/08636 describes a process for racemate resolution of primary andsecondary amines by enzyme-catalyzed acylation. Other publicationsdescribing processes for enzyme-catalyzed racemate resolution of aminesare, for example, WO 96/23894, WO 97/20946, WO 97/2871, WO 97/46698 andWO 98/03465.

The publications mentioned above describe various methods for racemateresolution of amines. In addition to the actual product of value, ineach racemate resolution 50% of the unwanted enantiomer are formed. Foran economical utilization of these processes it is important that thisunwanted enantiomer can be racemized and recycled into the racemateresolution process, or else that this initially unwanted enantiomer islikewise a compound in demand for chemical syntheses and accordingly aproduct of value. In the enzymatic racemate resolution, one of theenantiomers is obtained in the form of the amide. If this amide is theproduct of value, it has to be cleaved with the stereocenter beingretained. Such a process for cleaving optically active amides whileretaining the stereocenter is described, for example, in U.S. Pat. No.5,905,167.

The provision of the racemic aminoalcohol which is used as startingmaterial for the racemate resolution continues to be an essentialproblem for the industrial racemate resolution of optically activefunctionalized amines, such as aminoalcohols. For an economical process,a simple, safe and inexpensive synthetic route to the racemicfunctionalized amine is required. Murata et al. (J. Chem. Soc. Jpn.,Ind. Chem. Sect. 56 (1953): 628, Chem. Abstr. 49 (1955), 7517 g)describe a process for preparing 1-benzyloxy-3-butanone from3-buten-2-one using 3 equivalents of benzyl alcohol and 0.04 mol % of Namethoxide. This method has the disadvantage that the excess benzylalcohol has to be removed in an additional process step. Moreover, whencarrying out the process, the product is frequently cleaved again intothe starting materials, i.e. the consistency required for an industrialprocess is missing.

The prior-art processes for racemate resolution and the synthesis of theracemic functionalized amines have the disadvantage that they lack thesimplicity and consistency required for industrial utilization and that,accordingly, they can only be carried out under highly specificconditions. Moreover, they require considerable amounts of startingmaterials for the synthesis of the racemic educt, making a process basedthereon uneconomical.

It is an object of the present invention to provide a process forsynthesizing racemic functionalized amines, such as amino alcohols, anda process based thereon for the racemate resolution of the racemicamines which ensures high consistency and high enantioselectivity in theracemate resolution and can be used in a wide range of reactionconditions, using relatively low amounts of starting material andcatalyst, thus lowering the costs of the overall process even further.

We have found that this object is achieved by a process for preparingcompounds of the formula I

-   -   which comprises the following process steps:    -   a) A reaction of compounds of the formula II    -    with compounds of the formula R²—XH (III) in the presence of a        base to give compounds of the formula IV    -   b) A reaction of the reaction solution of compounds of the        formula IV with a compound of the formula NH₂R³ (V) to give        compounds of the formula VI    -   c) A hydrogenation of compounds of the formula VI in the        presence of a hydrogenation catalyst to give compounds of the        formula VII    -   d) A resolution of a racemate of compounds of the formula VII        using an optically active carboxylic acid or esters of the        formula VIII    -    in the presence of a lipase or esterase, giving compounds of        the formula I where the substituents and variables in the        formulae I, II, III, IV, V, VI, VII and VIII are as defined        below:    -   R¹ is substituted or unsubstituted, branched or unbranched        C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, arylalkyl, aryl,        hetarylalkyl or hetaryl,    -   R² is substituted or unsubstituted, branched or unbranched        C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl, C₃-C₁₀-alkynyl, arylalkyl, aryl,        hetarylalkyl or hetaryl,    -   R³ is hydrogen, hydroxyl, substituted or unsubstituted, branched        or unbranched C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl or C₃-C₁₀-alkynyl,    -   R⁴ is substituted or unsubstituted, branched or unbranched        C₁-C₁₀-alkyl,    -   R⁵ is hydrogen, substituted or unsubstituted, branched or        unbranched C₁-C₁₀-alkyl,    -   R⁶ is hydrogen, substituted or unsubstituted, branched or        unbranched C₁-C₁₀-alkyl or substituted or unsubstituted phenyl,    -   X=oxygen or nitrogen, preferably nitrogen    -   n=0 or 1.

In the compounds of the formulae I, II, IV, VI, VII and IX, R¹ issubstituted or unsubstituted, branched or unbranched C₁-C₁₀-alkyl,C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, arylalkyl, aryl, hetarylalkyl orhetaryl. Preferred radicals of R¹ are substituted or unsubstituted,branched or unbranched C₁-C₁₀-alkyl or aryl.

Alkyl radicals which may be mentioned are substituted or unsubstituted,branched or unbranched C₁-C₁₀-alkyl chains, such as, for example,methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl,n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, n-heptyl, n-octyl, n-nonyl or n-decyl. Preferredradicals are methyl, ethyl or propyl.

Alkenyl radicals which may be mentioned are branched or unbranchedC₂-C₁₀-alkenyl chains, such as, for example, ethenyl, propenyl,1-butenyl, 2-butenyl, 3-butenyl, 2-methylpropenyl, 1-pentenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl,2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl,2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl,1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl,1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl,3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl,2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl,4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl,3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl,1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl,1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl,1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl,2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl,3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl,1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl,2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl,1-ethyl-2-methyl-2-propenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl,4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl,4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, nonenyl or decenyl.

Alkynyl radicals which may be mentioned are branched or unbranchedC₂-C₁₀-alkynyl chains, such as, for example, ethynyl, prop-1-yn-1-yl,prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl,n-but-2-yn-1-yl, n-pent-1-yn-1-yl, n-pent-1-yn-3-yl, n-pent-1-yn-4-yl,n-pent-1-yn-5-yl, n-pent-2-yn-1-yl, n-pent-2-yn-4-yl, n-pent-2-yn-5-yl,3-methyl-but-1-yn-3-yl, 3-methyl-but-1-yn-4-yl, n-hex-1-yn-1-yl,n-hex-1-yn-3-yl, n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl,n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl,n-hex-3-yn-1-yl, n-hex-3-yn-2-yl, 3-methylpent-1-yn-1-yl,3-methylpent-1-yn-3-yl, 3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl,4-methylpent-1-yn-1-yl, 4-methylpent-2-yn-4-yl or4-methylpent-2-yn-5-yl.

Advantageously, the multiple bond of the alkenyl or alkynyl radicalsshould not be in the position alpha to the carbonylcarbon since thiswould have an adverse effect on the selectivity of the reaction [processstep (a)] and may necessitate a purification of the reaction products.In this case, the selectivity can be influenced positively byelectron-donating and/or bulky radicals, such as tert-butyl.

Suitable substituents of the abovementioned radicals of R¹ are, inprinciple, all feasible substituents except for ketones or aldehydes,for example one or more substituents such as halogen, for examplefluorine, amino, hydroxyl, alkyl, cycloalkyl, aryl, alkoxy, benzyloxy,phenyl or benzyl.

Arylalkyl radicals which may be mentioned are branched or straight-chainphenyl-(C₁-C₅-alkyl) or naphthyl-(C₁-C₅-alkyl) radicals, such asphenylmethyl, phenylethyl, phenylpropyl, phenyl-1-methylethyl,phenylbutyl, phenyl-1-methylpropyl, phenyl-2-methylpropyl,phenyl-1,1-dimethylethyl, phenylpentyl, phenyl-1-methylbutyl,phenyl-2-methylbutyl, phenyl-3-methylbutyl, phenyl-2,2-dimethylpropyl,phenyl-1-ethylpropyl, naphthylmethyl, naphthylethyl, naphthylpropyl,naphthyl-1-methylethyl, naphthylbutyl, naphthyl-1-methylpropyl,naphthyl-2-methylpropyl, naphthyl-1,1-dimethylethyl, naphthylpentyl,naphthyl-1-methylbutyl, naphthyl-2-methylbutyl, naphthyl-3-methylbutyl,naphthyl-2,2-dimethylpropyl, or naphthyl-1-ethylpropyl, and theirisomeric or stereoisomeric forms. Preferred radicals are branched orstraight-chain phenyl-(C₁-C₅-alkyl) radicals, such as phenylmethyl,phenylethyl or phenylpropyl.

Aryl radicals which may be mentioned are, for example, phenyl,methoxyphenyl or naphthyl, or aromatic rings or ring systems having 6 to18 carbon atoms in the ring system and up to 24 other carbon atoms whichmay form other non-aromatic rings or ring systems having 3 to 8 carbonatoms, which may be unsubstituted or substituted by one or moreradicals, such as halogen, for example fluorine, amino, hydroxyl, alkyl,alkoxy or other radicals. Preference is given to unsubstituted orsubstituted phenyl, methoxyphenyl or naphthyl.

Hetaryl(alkyl) radicals which may be mentioned are, for example,hetarylalkyl radicals which contain one or more nitrogen, sulfur and/oroxygen atoms in the ring or ring system and are attached to a branchedor unbranched C₁-C₅-alkylene chain, such as methylene, ethylene,n-propylene, 1-methylethylene, n-butylene, 1-methylpropylene,2-methylpropylene, 1,1-dimethylethylene, n-pentylene, 1-methylbutylene,2-methylbutylene, 3-methylbutylene, 2,2-dimethylpropylene or1-ethylpropylene.

Hetaryl radicals which may be mentioned are simple or fused aromaticring systems having one or more heteroaromatic 3- to 7-membered ringswhich may contain one or more heteroatoms, such as N, O and S, and whichmay be unsubstituted or substituted by one or more radicals, such ashalogen, for example fluorine, amino, hydroxyl, thio, alkyl, alkoxy orother aromatic or other saturated or unsaturated non-aromatic rings orring systems.

In the compounds of the formulae I, III, IV, VI, VII and IX, R² issubstituted or unsubstituted, branched or unbranched C₁-C₁₀-alkyl,C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, arylalkyl, aryl, hetarylalkyl orhetaryl. Preferred radicals of R¹ are substituted or unsubstituted,branched or unbranched C₁-C₁₀-alkyl or arylalkyl.

Alkyl radicals which may be mentioned are substituted or unsubstituted,branched or unbranched C₁-C₁₀-alkyl chains, such as, for example,methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl-,2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl,n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, n-heptyl, n-octyl, n-nonyl or n-decyl. Preferredradicals are methyl, ethyl or propyl.

Alkenyl radicals which may be mentioned are branched or unbranchedC₃-C₁₀-alkenyl chains, such as, for example, 2-propenyl, 2-butenyl,3-butenyl, 2-methylpropenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl,1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl,2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl,4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl,3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl,1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl,2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-2-butenyl,1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl,2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-2-propenyl, 2-heptenyl,3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-octenyl, 3-octenyl,4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, nonenyl or decenyl.Preferred radicals are 2-propenyl or 2-butenyl.

Alkynyl radicals which may be mentioned are branched or unbranchedC₃-C₁₀-alkynyl chains, such as, for example, prop-2-yn-1-yl,n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-pent-1-yn-3-yl, n-pent-1-yn-4-yl,n-pent-1-yn-5-yl, n-pent-2-yn-1-yl, n-pent-2-yn-4-yl, n-pent-2-yn-5-yl,3-methyl-but-1-yn-3-yl, 3-methyl-but-1-yn-4-yl, n-hex-1-yn-3-yl,n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl,n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-1-yl,n-hex-3-yn-2-yl, 3-methylpent-1-yn-3-yl, 3-methylpent-1-yn-4-yl,3-methylpent-1-yn-5-yl, 4-methylpent-2-yn-4-yl or4-methylpent-2-yn-5-yl. The preferred radical is prop-2-yn-1-yl.

Suitable substituents of the abovementioned radicals of R² are, inprinciple, all feasible substituents, for example one or moresubstituents such as halogen, for example fluorine, amino, hydroxyl,alkyl, cycloalkyl, aryl, alkoxy, benzyloxy, phenyl or benzyl.

Arylalkyl radicals which may be mentioned are branched or straight-chainphenyl-(C₁-C₅-alkyl) or naphthyl-(C₁-C₅-alkyl) radicals, such asphenylmethyl, phenylethyl, phenylpropyl, phenyl-1-methylethyl,phenylbutyl, phenyl-1-methylpropyl, phenyl-2-methylpropyl,phenyl-1,1-dimethylethyl, phenylpentyl, phenyl-1-methylbutyl,phenyl-2-methylbutyl, phenyl-3-methylbutyl, phenyl-2,2-dimethylpropyl,phenyl-1-ethylpropyl, naphthylmethyl, naphthylethyl, naphthylpropyl,naphthyl-1-methylethyl, naphthylbutyl, naphthyl-1-methylpropyl,naphthyl-2-methylpropyl, naphthyl-1,1-dimethylethyl, naphthylpentyl,naphthyl-1-methylbutyl, naphthyl-2-methylbutyl, naphthyl-3-methylbutyl,naphthyl-2,2-dimethylpropyl, or naphthyl-1-ethylpropyl, and theirisomeric or stereoisomeric forms. Preferred radicals are phenylmethyl,phenylethyl or naphthylmethyl.

Aryl radicals which may be mentioned are, for example, phenyl,methoxyphenyl or naphthyl, or aromatic rings or ring systems having 6 to18 carbon atoms in the ring system and up to 24 other carbon atoms whichmay form other non-aromatic rings or ring systems having 3 to 8 carbonatoms in the ring, which may be unsubstituted or substituted by one ormore radicals, such as halogen, for example fluorine, amino, hydroxyl,alkyl, alkoxy or other radicals. Preference is given to unsubstituted orsubstituted phenyl, methoxyphenyl or naphthyl.

Hetaryl(alkyl) radicals which may be mentioned are, for example,hetarylalkyl radicals which contain one or more nitrogen, sulfur and/oroxygen atoms in the ring or ring system and are attached to a branchedor unbranched C₁-C₅-alkylene chain, such as methylene, ethylene,n-propylene, 1-methylethylene, n-butylene, 1-methylpropylene,2-methylpropylene, 1,1-dimethylethylene, n-pentylene, 1-methylbutylene,2-methylbutylene, 3-methylbutylene, 2,2-dimethylpropylene or1-ethylpropylene.

Hetaryl radicals which may be mentioned are simple or fused aromaticring systems having one or more heteroaromatic 3- to 7-membered ringswhich may contain one or more heteroatoms, such as N, O and S, and whichmay be unsubstituted or substituted by one or more radicals, such ashalogen, for example fluorine, amino, hydroxyl, thio, alkyl, alkoxy orother aromatic or other saturated or unsaturated non-aromatic rings orring systems.

In the compounds of the formulae I, V, VI, VII and IX, R³ is hydrogen,hydroxyl, substituted or unsubstituted, branched or unbranchedC₁-C₁₀-alkyl, C₃-C₁₀-alkenyl or C₃-C₁₀-alkynyl. Preferred radicals arehydrogen or hydroxyl.

Alkyl radicals which may be mentioned are substituted or unsubstituted,branched or unbranched C₁-C₁₀-alkyl chains, such as, for example,methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl,n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, n-heptyl, n-octyl, n-nonyl or n-decyl. Preferredradicals are methyl, ethyl or propyl.

Alkenyl radicals which may be mentioned are branched and unbranchedC₃-C₁₀-alkenyl chains, such as, for example, propenyl, 2-butenyl,3-butenyl, 2-methylpropenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl,1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl,2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl,4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl,3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl,1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl,2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-2-butenyl,1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl,2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-2-propenyl, 2-heptenyl,3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-octenyl, 3-octenyl,4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, nonenyl or decenyl.

Alkynyl radicals which may be mentioned are branched or unbranchedC₃-C₁₀-alkynyl chains, such as, for example, prop-2-yn-1-yl,n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-3-yl,n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl, n-pent-2-yn-4-yl,n-pent-2-yn-5-yl, 3-methyl-but-1-yn-3-yl, 3-methyl-but-1-yn-4-yl,n-hex-1-yn-3-yl, n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl,n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl,n-hex-3-yn-1-yl, n-hex-3-yn-2-yl, 3-methylpent-1-yn-3-yl,3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4-methylpent-2-yn-4-ylor 4-methylpent-2-yn-5-yl.

Suitable substituents of the abovementioned radicals of R³ are, inprinciple, all feasible substituents, for example one or moresubstituents such as halogen, for example fluorine, amino, hydroxy,alkyl, cycloalkyl, aryl, alkoxy, benzyloxy, phenyl or benzyl.

In the compounds of the formula VIII, R⁴ is substituted orunsubstituted, branched or unbranched C₁-C₁₀-alkyl.

Alkyl radicals which may be mentioned are substituted or unsubstituted,branched or unbranched C₁-C₁₀-alkyl chains, such as, for example,methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl,n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, n-heptyl, n-octyl, n-nonyl or n-decyl. Preferredradicals are methyl, ethyl, 1-methylethyl, propyl, butyl or pentyl.

Suitable substituents of the abovementioned radicals of R⁴ are, inprinciple, all feasible substituents, for example one or moresubstituents such as halogen, for example fluorine, chlorine or bromine,cyano, nitro, amino, hydroxyl, alkyl, cycloalkyl, aryl, alkoxy,benzyloxy, phenyl or benzyl. Preferred substituents are halogen, such aschlorine or bromine, cyano, benzyloxy, C₁-C₄-alkyl or hydroxyl.

In the compounds of the formulae VIII and IX, R⁵ is hydrogen,substituted or unsubstituted, branched or unbranched C₁-C₁₀-alkyl.

Alkyl radicals which may be mentioned are substituted or unsubstituted,branched or unbranched C₁-C₁₀-alkyl chains, such as, for example,methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl,n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, n-heptyl, n-octyl, n-nonyl or n-decyl. Preferredradicals are hydrogen, methyl, ethyl or propyl.

Suitable substituents of the abovementioned radicals of R⁵ are, inprinciple, all feasible substituents, for example one or moresubstituents such as halogen, for example fluorine, chlorine or bromine,cyano, nitro, amino, hydroxyl, alkyl, cycloalkyl, aryl, alkoxy,benzyloxy, phenyl or benzyl.

In the compounds of the formulae VIII and IX, R⁶ is hydrogen,substituted or unsubstituted, branched or unbranched C₁-C₁₀-alkyl orsubstituted or unsubstituted phenyl.

Alkyl radicals which may be mentioned are substituted or unsubstituted,branched or unbranched C₁-C₁₀-alkyl chains, such as, for example,methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl,n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, n-heptyl, n-octyl, n-nonyl or n-decyl.

Preferred radicals are methyl, ethyl or propyl. Suitable substituents ofthe abovementioned radicals of R⁶ are, in principle, all feasiblesubstituents, for example one or more substituents such as halogen, forexample fluorine, chlorine or bromine, cyano, nitro, amino, hydroxyl,alkyl, cycloalkyl, aryl, alkoxy, benzyloxy, phenyl or benzyl.

The invention furthermore relates to a process for preparing compoundsof the formula VII

-   -   which comprises the following process steps:    -   a) A reaction of compounds of the formula II    -    with compounds of the formula R²—XH (III) in the presence of a        base to give compounds of the formula IV    -   b) A reaction of the reaction solution of compounds of the        formula IV with a compound of the formula NH₂R³ (V) to give        compounds of the formula VI    -   c) A hydrogenation of compounds of the formula VI in the        presence of a hydrogenation catalyst to give compounds of the        formula VII, where the substituents and variables in the        formulae II, III, IV, V, VI and VII are as defined in claim 1.

For clarity, scheme I shows the processes according to the invention inan exemplary manner. Process steps (a) to (d) correspond to the processfor preparing functionalized optically active amines, for exampleoptically active aminoalcohols or optically active diamines. The processsteps (a) to (c) correspond to the process for preparing functionalizedracemic amines which can subsequently be subjected to racemateresolution. In scheme I, this racemate resolution is shown using theexample of enzymatic racemate resolution. However, it can also becarried out using other processes for racemate resolution, such as theclassical chemical racemate resolution via diastereomeric salts, or viachromatographic processes. The variables and substituents used in schemeI are as defined above. The scheme furthermore shows the optionalpossibility of neutralizing the reaction solution obtained in step (a)prior to the reaction with compounds of the structure or formula NH₂R³(V). If the compounds of the formula R²—XH (III) are employed in a largeexcess, based on the reaction partner (II), it is necessary toneutralize the reaction solution prior to further reaction, sinceotherwise an undesirable cleavage of the reaction product into thestarting materials occurs when the excess compound R²—XH is removed.This cleavage results in a loss of yield, and the product has to bepurified. If the advantageous amount, according to the invention, of thecompound (III) of from 0.5 to 2.5 equivalents, preferably from 0.5 to2.0; particularly preferably from 0.7 to 1.5; very particularlypreferably from 0.9 to 1.1 equivalents, based on the reaction partner(II), is employed, it is not necessary to reduce the amount of excessR²—XH, and neutralization of the reaction solution prior to the reactionstep b is advantageously not necessary in the processes according to theinvention. However, depending on the starting materials, neutralizationmay advantageously be carried out to increase the consistency of theprocess. Acids suitable for the neutralization are all customary mineralacids, such as HCl, H₂SO₄ or H₃PO₄, or organic acids, such as loweraliphatic carboxylic acids, for example formic acid. Preference is givento using orthophosphoric acid.

Suitable bases for process step (a) of the process according to theinvention are, in principle, all bases which can catalyze the additionof the compound (III) to the Michael system of the compound (II), suchas NaOH, KOH, tertiary amines or alkali metal alkoxides or alkalineearth metal alkoxides. Bases which may be mentioned as beingadvantageous are alkali metal alkoxides and alkaline earth metalalkoxides, such as sodium methoxide, sodium ethoxide, sodium butoxide,sodium tert-butoxide, potassium tert-butoxide, or strong basic amines,such as diazabicycloundecene. As catalyst, the base is advantageouslyemployed in a concentration of from 0.001 to 10 mol %, preferably from0.01 to 5 mol %, particularly preferably from 0.3 to 0.5 mol %, based onthe compound (III) used.

Process step (a) of the processes according to the invention can becarried out in the presence of an aprotic solvent which is inert underthe reaction conditions. Examples of suitable solvents are hydrocarbons,such as hexane, cyclohexane, benzene or toluene, or ethers, such asmethyl tert-butyl ether (=MTBE), diethyl ether, dibutyl ether ortetrahydrofuran (=THF). The reaction is advantageously carried out inthe absence of a solvent.

The reaction [process step (a)] is advantageously carried out at from−30 to +50° C., preferably from −5 to +10° C.

Advantageous compounds of the formula (V) are, in addition to ammonia,primary and secondary aliphatic amines and hydroxylamine. Process step(b) is advantageously carried out using hydroxylamine, which is employedas aqueous solution, or as an aqueous solution of its salt, such as, forexample, hydroxylamine hydrochloride, hydroxylamine sulfate, ifappropriate, as for the other compounds of the formula (V), in thepresence of a base, such as aqueous sodium hydroxide solution or sodiumacetate. Preference is given to using an aqueous solution of the freehydroxylamine. The reaction can advantageously be carried out in aninert protic solvent, such as water or an alcohol, for example methanol,ethanol, propanol, butanol or isobutanol. The reaction is preferablycarried out in water.

The reaction [process step (b)] is advantageously carried out at from 0to +100° C., preferably from 20 to 40° C.

The hydrogenation in the processes according to the invention [processstep (c)] can be carried out using all customary hydrogenation catalystsbased, for example, on Ni, Co, Hg, Pt, Pd, Ru or Rh. One of thecatalysts customarily used for homogeneous catalysis is, for example,Wilkinson's catalyst. The hydrogenation can be carried out underheterogeneous or homogeneous catalysis. For economical reasons andbecause it is readily available, the preferred catalyst is Raney nickel.The hydrogenation is advantageously carried out in a solvent which isinert under the reaction conditions. Such solvents are, for example,hydrocarbons, such as hexane, cyclohexane, benzene or toluene, ethers,such as MTBE, diethyl ether, dibutyl ether or THF, or alcohols, such asmethanol, ethanol, propanol, butanol or iso-butanol. Preferred solventsare THF or methanol.

The reaction [process step (c)] is advantageously carried out at from 0to +150° C., preferably from 50 to 100° C. The hydrogenation is usuallycarried out in a pressure range of from atmospheric pressure to 300 bar.The reaction is preferably carried out at a pressure of from 50 to 150bar.

As described above, the racemate resolution can be carried out viaenzymatic or classical chemical racemate resolution, including the useof chromatographic methods. The racemate resolution is preferablycarried out with the aid of enzymes or diastereomeric salts,particularly preferably using enzymes.

For the separation via diastereomeric salts, all optically activecarboxylic acids are suitable in principle. Advantageous opticallyactive carboxylic acids are tartaric acid, dibenzoyltartaric acid,mandelic acid, camphoric acid, camphorsulfonic acid, p-hydroxymandelicacid, p-Cl-mandelic acid, phenoxypropionic acid,p-hydroxyphenoxypropionic acid or lactic acid. Preference is given tousing mandelic acid for the racemate resolution. The salt formation canbe carried out in an inert solvent, such as a hydrocarbon, for examplehexane, cyclohexane, benzene or toluene; or an ether, for example MTBE,diethyl ether, dibutyl ether or THF; or an alcohol, for examplemethanol, ethanol, propanol, isopropanol, butanol or isobutanol. Forrecrystallization, it is advantageous to employ an alcohol, such asmethanol, ethanol, propanol, isopropanol, butanol or isobutanol.Preference is given to using isopropanol. To improve crystallization,the solution can be cooled. If the salt formed precipitatesspontaneously, it is redissolved by heating and slowly recrystallizedwith cooling. If required, the crystallization can be carried out anumber of times.

The racemate resolution of the functionalized amines can advantageouslyalso be carried out via enzymes such as esterases or lipases.

Esterases and lipases which are suitable for the process according tothe invention are, in principle, all lipases and esterases availablefrom plants, animals or microorganisms. It is advantageous to usemicrobial lipases which can be isolated, for example, from eucaryoticorganisms, such as fungi or yeasts, or procaryotic organisms, such asbacteria. Bacterial lipases from the genera Bacillus or Pseudomonas, forexample Amano P or the lipase from Pseudomonas spec. DSM 8246, orlipases from fungi such as Aspergillus or from yeasts such as Candida orYerrowia, are particularly suitable. Further advantageous lipases are,for example, the enzymes which are commercially available from NovoNordisk, in particular the lipases SP 523, SP 524, SP 525, SP 526 andNovozym® 435, which are obtained from yeasts, such as Candidaantarctica. Other examples are the lipases Chirazyme L1, L2, L3, L4, L5,L6, L7 and L8 which are commercially available from Roche MolecularBiochemicals (Roche Diagnostic GmbH, Penzberg).

The lipases can be employed in native or immobilized form. Theimmobilized lipases can be microencapsulated, emulsified withprepolymers and polymerized, crosslinked with bifunctional substances(oligomers, aldehydes etc.) or attached to inorganic or organiccarriers, such as, for example, Celite, Lewatit, zeolites,polysaccharides, polyamides or polystyrene resins. Particular preferenceis given to the lipases Novozym® 435 and Chirazyme L2.

The reaction with the esterases or lipases is generally carried outunder atmospheric pressure, if appropriate under inert gas, such asnitrogen or argon. However, it can also be carried out under elevatedpressure.

The temperature for the reaction of the racemic amines of the formulaVII with the esters suitable for the racemate resolution, which carry anoxygen atom in the position alpha to the carbonyl carbon, specificallythe esters of the formula VIII

is usually from 0 to 90° C., preferably from 10 to 60° C., particularlypreferably from 20 to 50° C. The substituents of the preferred estersVIII are as defined above.

The reaction of the ester with the racemic functionalized amine, i.e.the corresponding aminoalcohol or diamine, under enzyme catalysis isusually carried out at room temperature. Depending on the substrate, thereaction times are from 1 to 48 hours. Secondary aminoalcohols ordiamines generally require longer reaction times than primaryaminoalcohols or diamines. The lower reactivity of secondary amines canalso be compensated by an increased amount of catalyst, compared toprimary amines.

From 0.5 to 2.0 mol, preferably from 0.5 to 1 mol, of ester are employedper mole of racemic amine. The amount of enzyme required depends on theactivity of the enzyme preparation and the reactivity of the amine andcan easily be determined by preliminary experiments. In general, from0.1 to 10% by weight, preferably from 1 to 5% by weight, of theimmobilized enzyme preparation (based on the racemic amine) areemployed. Novozym® 435 has an activity of about 7000 PL U/g-10,000 PLU/g (PL=propyl laurate units, the units are based on the substratepropyl laurate).

The amount of enzyme that has to be added depends on the type of enzymeand the activity of the enzyme preparation. The optimum amount of enzymefor the reaction can easily be determined by simple preliminaryexperiments.

The course of the reaction can easily be monitored by customary methods,such as gas chromatography or high pressure liquid chromatography. Ifthe desired conversion, generally 50%, has been achieved, the reactionis terminated, preferably by removing the catalyst, for example byfiltering off the (supported) enzyme. The reaction can also beterminated, for example, by addition of enzyme-destroying substances,such as acids or bases, or by heating. If the reaction is carried outcontinuously, the conversion can be controlled by the enzyme load, i.e.the amount of amine which is pumped through the enzyme reactor per timeunit. The process can preferably be carried out continuously, but alsobatch-wise or semi-continuously.

The enzyme-catalyzed racemate resolution can be carried out in protic oraprotic solvents or else without addition of solvents. Suitable solventsare, for example, hydrocarbons such as hexane, cyclohexane or toluene,ethers, such as, for example, diethyl ether, dioxane, methyl tert-butylether, tert-amyl methyl ether or THF, nitrites, such as acetonitrile,butyronitrile, alcohols, such as tert-butanol, 3-methyl-3-pentanol, andhalogenated hydrocarbons, such as, for example, methylene chloride.

The reaction proceeds particularly well when the solvents and startingmaterials are as anhydrous as possible. For the racemate resolution, thesolvents and starting materials amine and ester are advantageouslydried. In principle this can be carried out in any manner known to theperson skilled in the art, for example by azeotropic drying or by usingdrying agents, such as sodium sulfate, magnesium sulfate, KOH,phosphorus pentoxide, molecular sieves, silica gel or alumina.

After the enzyme-catalyzed racemate resolution has ended, a mixture ofthe acylated amine enantiomer of the formula IX

the unreacted amine enantiomer, the alcohol released from the esterduring acylation and possibly excess ester is present. Suitable forseparating this mixture are, in particular, distillative and extractivemethods. Thus, low-boiling amines can be distilled off directly from thereaction mixture. The amide can subsequently be separated offdistillatively or extractively from the alcohol and, if appropriate, theester and can then be hydrolyzed in a customary manner, for example byboiling with aqueous sodium hydroxide or potassium hydroxide solution,with racemization or else without racemization (see U.S. Pat. No.5,905,167). In columns 2 to 5 and in Example 2, U.S. Pat. No. 5,905,167describes a method for cleaving amides with retention of thestereocenter. The second amine enantiomer formed in the hydrolysis canbe isolated distillatively or extractively from the carboxylic acid,which is present as a salt. The isolation is preferably carried out byextraction, using, as extractant, ethers, such as diethyl ether, methyltert-butyl ether and dibutyl ether, halogenated hydrocarbons, such asdichloromethane or trichloroethylene, or hydrocarbons, such as pentane,hexane, cyclohexane, benzene, toluene and xylene. A likewise preferredembodiment of the isolation of the amine is steam distillation. Aparticularly suitable embodiment of the invention comprises carrying outthe cleavage at a temperature which is sufficiently high to distil overthe resulting reaction product (amine) together with the steam, so thatit is removed immediately from the reaction mixture, whereas the acid,which is dissociated under the alkaline conditions, remains in theflask. By the routes mentioned, it is, in principle, possible to work upamines in the processes according to the invention.

The resulting free amine can either be used as a further product ofvalue for further syntheses or else advantageously be recycled afterracemization into the process at the stage of process step (d). Theamide cleaved directly with racemization can likewise advantageously berecycled into the process at this stage. In this manner, it istheoretically possible to convert the entire racemate into the desiredenantiomer. Such racemizations can be carried out, for example, underthe same conditions which are used for preparing amines from alcohols orketones (“reductive amination”). The acid formed during the hydrolysiscan, after acidification of the hydrolysis solution, be recovered,preferably extractively, and esterified by customary processes andrecycled.

The processes according to the invention are advantageously suitable forpreparing racemic aminoalcohols of the formula Ic and for resolvingtheir racemate via enantioselective acylation

in which the substituents are as defined above.

The invention furthermore relates to compounds of the formula I, VII andIX:

in which the substituents and variables in the formulae I, VII and IXare as defined above. Preferred compounds of the formulae I, VII and IXare the following compounds:

The processes according to the invention are not only suitable aspreparation processes for producing optically active primary andsecondary functionalized amines, such as aminoalcohols or diamines, butthey can also be a component of complicated chemical multi-stepsyntheses, for example in the preparation of rugs or crop protectionagents.

The examples below serve to illustrate the invention.

EXAMPLES

Example 1 Process Steps (a) and (b): Synthesis of1-benzyloxy-3-butanoneoxime (Scheme III)

At 0° C., 648 g (6.0 mol) of benzyl alcohol were admixed with 2.6 g (24mmol) of potassium tert-butoxide, and the mixture was stirred for 30minutes. Over a period of 30 minutes, 441 g (6.3 mol) of freshlydistilled methyl vinyl ketone were added dropwise, the temperature beingmaintained at 0-10° C. by cooling. After the addition had ended, themixture was stirred at 10° C. for another hour. 2.8 g (24 mmol) oforthophosphoric acid (as an 85% strength aqueous solution) were thenadded dropwise. The mixture was warmed to room temperature (=23° C.).

According to ¹H-NMR, 1-benzyloxy-3-butanone was formed in the reaction(¹H-NMR: δ=2.05 (s; 3H), 2.60 (t, J=7.0 Hz; 2H), 3.65 (t, J=7.0 Hz; 2H),4.45 (s, 2H), 7.25 (m, 5H).

With vigorous stirring, 471 g of a 51.7% strength aqueous solution (7.37mol) of hydroxylamine were added dropwise to the crude1-benzyloxy-3-butanone such that the reaction temperature remained atabout 35° C. The mixture was then stirred for another 15 hours. The nextday, the upper, aqueous phase was separated off and the lower, organicphase was taken up in 500 ml of toluene and heated on a water separatoruntil no more water distilled over. The solvent and volatile componentswere distilled off at 0.5 mm (bath temperature: 100° C.), giving as aresidue 1100 g (95%) of 1-benzyloxy-3-butanoneoxime as E/Z mixture.

Main Isomer (about 65%):

¹H-NMR: δ=1.90 (s; 3H), 2.50 (t, J=7.0 Hz; 2H), 3.65 (t, J=7.0 Hz; 2H),4.50 (s, 2H), 7.30 (m, 5H), 9.30 (s, broad, 1H).

Minor Isomer (about 35%):

¹H-NMR: δ=1.95 (s; 3H), 2.75 (t, J=7.0 Hz; 2H), 3.65 (t, J=7.0 Hz; 2H),4.50 (s, 2H), 7.30 (m, 5H), 9.30 (s, broad, 1H).

Example 2 Hydrogenation to 1-benzyloxy-3-aminobutane (=rac. BOBA)[Process Step (c), Scheme IV]

In an autoclave, 100 g of Raney nickel were initially charged in 300 mlof THF, and the mixture was admixed with a solution of 850 g (4.4 mol)of 1-benzyloxy-3-butanoneoxime in 2.5 l of THF. The autoclave waspressurized with 100 bar of hydrogen and heated with stirring to 80° C.An exothermic reaction started and the pressure was kept constant bymetered addition of hydrogen gas. After the hydrogen uptake had ended,the pressure was increased to 150 bar and stirring was continued for 4hours. The autoclave was then cooled, the stirrer was switched off andthe slightly turbid product solution was decanted off from the catalystand filtered through kieselguhr. The clear filtrate was freed from thesolvent using a rotary evaporator. The less volatile residue wassubsequently subjected to fractional distillation under an oil pumpvacuum. At 1.3 mm/85-87° C., the product rac-BOBA distils over as aclear liquid.

Yield: 646 g (83%)

¹H-NMR: δ=1.05 (d, J=7 Hz; 3H), 1.35 (s, broad; 2H), 1.65 (mc; 2H), 3.10(mc; 1H), 3.55 (mc; 2H), 4.50 (s, 2H), 7.30 (m, 5H).

Example 3 Racemate Resolution [Process Step (d)]

A. Enantiomer Analysis of BOBA:

Derivatization (Scheme V):

0.5 g of amine was dissolved in 25 ml of diethyl ether. The solution wascooled to 0° C. and 0.2 ml of benzoyl chloride was added all at once. Atroom temperature, the mixture was stirred for 30 minutes and thenadmixed with 10 ml of water. The aqueous phase was separated off and theupper, organic phase was washed successively with 10 ml each of 10%strength hydrochloric acid, water and saturated sodium bicarbonatesolution. The reaction solution was dried over sodium sulfate. 1 ml ofthe solution was then diluted with 5 ml of n-hexane and analyzed by HPLCchromatography.Scheme V: Derivatization

-   Column: Chiralcel OD Daicel Chemical Industries, Ltd.-   Temperature: room temperature-   Detector: absorption at 214 nm-   Amount injected: 20 μl-   Mobile phase: n-hexane/isopropanol/ethanol (300:50:0.8 v/v/v)-   Flow rate: 1.3 ml/min (at about 40 kg/cm²)    Retention Times:

Example 4 Racemate Resolution by Crystallization

A solution of 2.15 g (35.6 mmol) of acetic acid and 5.4 g (35.6 mmol) ofD-mandelic acid in 50 ml of isopropanol was added dropwise to a solutionof 12.8 g (71.5 mmol) of rac-BOBA in 70 ml of isopropanol. Theprecipitated solid was redissolved by heating and then allowed to standfor recrystallization.

From a sample of the salt, which had been filtered off with suction, thebound amine was freed by treatment with aqueous sodium hydroxidesolution.

According to HPLC analysis, the S-BOBA had an ee value of 50.5%. Theprecipitated salt was then recrystallized once more from 100 ml ofisopropanol. The amine was then freed from the resulting salt bytreatment with 10 ml of 50% strength sodium hydroxide solution andextracted with 50 ml of ether, and the extract was concentrated. Thisgave 2.2 g (34%) of S-BOBA. According to HPLC analysis, the enantiomericpurity was 90% ee.

Example 5 Racemate Resolution by Enzyme-Catalyzed Racemate Resolution

1500 g (8.43 mol) of rac-BOBA were cooled to 0° C. and admixed with 523g (3.96 mol) of isopropyl methoxyacetate. 75 g of Novozym 435® wereadded, and the mixture was warmed with stirring to room temperature(about 23° C.). After 15 hours, the catalyst was filtered off and washedwith 1 l of toluene. The filtrate was freed from volatile componentsunder reduced pressure (20 mbar) and then distilled in a thin-filmevaporator (1.0 mbar, 180° C.). S-BOBA passed over as overheaddistillate at (95-98° C.), R-BOBamide went into the distillation bottomas heavy boiler.

802.5 g (53%) of S-BOBA which, according to HPLC analysis, has anoptical purity of 90% ee were obtained.

964 g (45.5%) of R-BOBamide (opt. purity: 98% ee) were obtained asbottom.

R-BOBamide, ¹H-NMR: δ=1.20 (d, J=7 Hz; 3H), 1.65-1.95 (mc; 2H), 3.15 (s;3H), 3.50-3.70 (mc; 2H), 3.75 and 3.85 (AB system, J_(AB)=10.5 Hz; 2H),4.20 (mc; 1H), 4.50 (s, 2H), 6.90 (s, broad; 1H), 7.10-7.40 (m, 5H).

Example 6 Cleavage of the R-BOBamide

At 120° C., a mixture of 918 g (3.66 mol) of R-BOBamide and 900 g oftriethanolamine was admixed with 800 g (10 mol) of 50% strength sodiumhydroxide solution, and the mixture was stirred at this temperature for3 hours. After cooling, the mixture was diluted with 1.5 l of water andextracted three times with in each case 1 l of diethyl ether. Thecombined extracts were washed successively with 1 l of water and 100 mlof saturated NaCl solution, dried over Na₂SO₄ and then concentrated.This left a residue of 625 g (95%) of R-BOBA as a slightly yellow oil.

According to HPLC, the optical purity was 97% ee.

1-20. (canceled)
 21. A compound of the formula IX

wherein, R¹ is substituted or unsubstituted, branched or unbranchedC₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, arylalkyl, aryl,hetarylalkyl or hetaryl, R² is substituted or unsubstituted, branched orunbranched C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl, C₃-C₁₀-alkynyl, arylalkyl,aryl, hetarylalkyl or hetaryl, R³ is hydrogen, hydroxyl, substituted orunsubstituted, branched or unbranched C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl orC₃-C₁₀-alkynyl, R⁵ is hydrogen, substituted or unsubstituted, branchedor unbranched C₁-C₁₀-alkyl, R⁶ is hydrogen, substituted orunsubstituted, branched or unbranched C₁-C₁₀-alkyl or substituted orunsubstituted phenyl. X=oxygen or nitrogen, n=0 or
 1. 22. A compound ofthe formula IX

obtained by a process which comprises the following process steps: a)reaction of compounds of the formula II

with compounds of the formula R²—XH (III) in the presence of a base togive compounds of the formula IV

b) reaction of compounds of the formula IV with a compound of theformula NH₂R³ (V) to give compounds of the formula VI

c) hydrogenation of compounds of the formula VI in the presence of ahydrogenation catalyst to give compounds of the formula VII

d) resolution of a racemate of compounds of the formula VII using anoptically active carboxylic acid or esters of the formula VIII

in the presence of a lipase or esterase to obtain a mixture of opticallyactive heteroatom-substituted amine of the formula I

and optically active heteroatom-substituted amide of the formula IX, ande) separation of the mixture obtained in step (d), where R¹ issubstituted or unsubstituted, branched or unbranched C₁-C₁₀-alkyl,C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, arylalkyl, aryl, hetarylalkyl orhetaryl, R² is substituted or unsubstituted, branched or unbranchedC₁-C₁₀-alkyl, C₃-C₁₀-alkenyl, C₃-C₁₀alkynyl, arylalkyl, aryl,hetarylalkyl or hetaryl, R³ is hydrogen, hydroxyl, substituted orunsubstituted, branched or unbranched C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl orC₃-C₁₀-alkynyl, R⁴ is substituted or unsubstituted, branched orunbranched C₁-C₁₀-alkyl, R⁵ is hydrogen, substituted or unsubstituted,branched or unbranched C₁-C₁₀-alkyl, R⁶ is hydrogen, substituted orunsubstituted, branched or unbranched C₁-C₁₀-alkyl or substituted orunsubstituted phenyl, X=oxygen or nitrogen, n=0 or 1.